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ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . 4
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . 21
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
Analysis 1.1. Comparison 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by
mode of ventilation, Outcome 1 Death before discharge from hospital. . . . . . . . . . . . . . . 63
Analysis 1.2. Comparison 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by
mode of ventilation, Outcome 2 Death or bronchopulmonary dysplasia (BPD) (36 weeks). . . . . . . . 65
Analysis 1.3. Comparison 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by
mode of ventilation, Outcome 3 Failure of mode of ventilation. . . . . . . . . . . . . . . . . 66
Analysis 1.4. Comparison 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by
mode of ventilation, Outcome 4 Addition of neuromuscular paralysis where previously not paralysed. . . . 67
Analysis 1.5. Comparison 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by
mode of ventilation, Outcome 5 Duration of positive pressure ventilation (days, survivors). . . . . . . . 68
Analysis 1.6. Comparison 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by
mode of ventilation, Outcome 6 Duration of positive pressure ventilation (log data, survivors). . . . . . . 69
Analysis 1.7. Comparison 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by
mode of ventilation, Outcome 7 Inspired oxygen concentration % (study definition). . . . . . . . . . 70
Analysis 1.8. Comparison 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by
mode of ventilation, Outcome 8 Any pH < 7.25. . . . . . . . . . . . . . . . . . . . . . 71
Analysis 1.9. Comparison 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by
mode of ventilation, Outcome 9 Hypocarbia partial pressure of carbon dioxide (pCO2) < 35 mmHg/4.7 kPa. 72
Analysis 1.10. Comparison 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by
mode of ventilation, Outcome 10 Respiratory acidosis; pH < 7.25 and pCO2 > 8 kPa. . . . . . . . . . 73
Analysis 1.11. Comparison 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by
mode of ventilation, Outcome 11 Incidence of hypocarbia or respiratory acidosis. . . . . . . . . . . 74
Analysis 1.12. Comparison 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by
mode of ventilation, Outcome 12 Patent ductus arteriosus. . . . . . . . . . . . . . . . . . . 75
Analysis 1.13. Comparison 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by
mode of ventilation, Outcome 13 Air leak (any). . . . . . . . . . . . . . . . . . . . . . . 76
Analysis 1.14. Comparison 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by
mode of ventilation, Outcome 14 Pneumothorax. . . . . . . . . . . . . . . . . . . . . . 77
Analysis 1.15. Comparison 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by
mode of ventilation, Outcome 15 Pulmonary interstitial emphysema. . . . . . . . . . . . . . . 78
Analysis 1.16. Comparison 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by
mode of ventilation, Outcome 16 Any intraventricular haemorrhage (IVH). . . . . . . . . . . . . 79
Volume-targeted versus pressure-limited ventilation in neonates (Review) i
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.17. Comparison 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by
mode of ventilation, Outcome 17 Periventricular leukomalacia (PVL). . . . . . . . . . . . . . . 80
Analysis 1.18. Comparison 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by
mode of ventilation, Outcome 18 IVH grade 3-4. . . . . . . . . . . . . . . . . . . . . . 81
Analysis 1.19. Comparison 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by
mode of ventilation, Outcome 19 Any IVH or PVL. . . . . . . . . . . . . . . . . . . . . 82
Analysis 1.20. Comparison 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by
mode of ventilation, Outcome 20 IVH grade 3-4 or PVL. . . . . . . . . . . . . . . . . . . 83
Analysis 1.21. Comparison 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by
mode of ventilation, Outcome 21 BPD (supplemental oxygen in survivors at 36 weeks only). . . . . . . 84
Analysis 2.1. Comparison 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants weighing
less than 1000 g, Outcome 1 Death in hospital. . . . . . . . . . . . . . . . . . . . . . . 85
Analysis 2.2. Comparison 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants weighing
less than 1000 g, Outcome 2 Death or bronchopulmonary dysplasia (BPD) (36 weeks). . . . . . . . . 86
Analysis 2.3. Comparison 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants weighing
less than 1000 g, Outcome 3 Duration of positive pressure ventilation (days, survivors). . . . . . . . . 87
Analysis 2.4. Comparison 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants weighing
less than 1000 g, Outcome 4 Duration of positive pressure ventilation (log data, survivors). . . . . . . . 88
Analysis 2.5. Comparison 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants weighing
less than 1000 g, Outcome 5 Any pH < 7.25. . . . . . . . . . . . . . . . . . . . . . . . 89
Analysis 2.6. Comparison 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants weighing
less than 1000 g, Outcome 6 Hypocarbia partial pressure of carbon dioxide (pCO2) < 35 mmHg/4.7 kPa. . . 89
Analysis 2.7. Comparison 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants weighing
less than 1000 g, Outcome 7 Respiratory acidosis pH < 7.25 and pCO2 > 60 mmHg/8 kPa. . . . . . . 90
Analysis 2.8. Comparison 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants weighing
less than 1000 g, Outcome 8 Hypocarbia or respiratory acidosis. . . . . . . . . . . . . . . . . 91
Analysis 2.9. Comparison 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants weighing
less than 1000 g, Outcome 9 Patent ductus arteriosus. . . . . . . . . . . . . . . . . . . . . 92
Analysis 2.10. Comparison 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants
weighing less than 1000 g, Outcome 10 Air leak (any). . . . . . . . . . . . . . . . . . . . 93
Analysis 2.11. Comparison 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants
weighing less than 1000 g, Outcome 11 Pneumothorax. . . . . . . . . . . . . . . . . . . . 94
Analysis 2.12. Comparison 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants
weighing less than 1000 g, Outcome 12 Pulmonary interstitial emphysema. . . . . . . . . . . . . 95
Analysis 2.13. Comparison 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants
weighing less than 1000 g, Outcome 13 Any intraventricular haemorrhage (IVH). . . . . . . . . . . 96
Analysis 2.14. Comparison 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants
weighing less than 1000 g, Outcome 14 IVH grade 3-4. . . . . . . . . . . . . . . . . . . . 97
Analysis 2.15. Comparison 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants
weighing less than 1000 g, Outcome 15 Periventricular leukomalacia (PVL). . . . . . . . . . . . . 98
Analysis 2.16. Comparison 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants
weighing less than 1000 g, Outcome 16 Any IVH or PVL. . . . . . . . . . . . . . . . . . . 99
Analysis 2.17. Comparison 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants
weighing less than 1000 g, Outcome 17 IVH grade 3-4 or PVL. . . . . . . . . . . . . . . . . 100
Analysis 2.18. Comparison 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants
weighing less than 1000 g, Outcome 18 BPD (supplemental oxygen in survivors at 36 weeks). . . . . . . 101
Analysis 3.1. Comparison 3 Miscellaneous post hoc analyses, Outcome 1 Severe disability (any definition). . . . . 102
Analysis 3.2. Comparison 3 Miscellaneous post hoc analyses, Outcome 2 Severe disability (any definition) or death. . 102
Analysis 3.3. Comparison 3 Miscellaneous post hoc analyses, Outcome 3 Gross motor developmental issue (any
definition). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Analysis 3.4. Comparison 3 Miscellaneous post hoc analyses, Outcome 4 Steroids for bronchopulmonary dysplasia. . 103
Analysis 3.5. Comparison 3 Miscellaneous post hoc analyses, Outcome 5 Need for home oxygen (survivors). . . . 104
Claus Klingenberg1 ,2 , Kevin I Wheeler3,4 , Naomi McCallion5,6 , Colin J Morley7 , Peter G Davis8 ,9,10
1
Department of Pediatrics, University Hospital of North Norway, Tromsø, Norway. 2 Paediatric Research Group, UiT The Arctic
University of Norway, Tromsø, Norway. 3 Department of Neonatology, Royal Children’s Hospital Melbourne, Parkville, Melbourne,
Australia. 4 Murdoch Childrens Research Institute, Parkville, Australia. 5 Department of Paediatrics, Rotunda Hospital, Dublin, Ireland.
6 Department of Paediatrics, Royal College of Surgeons in Ireland, Dublin 2, Ireland. 7 Department of Obstetrics and Gynecology, Uni-
versity of Cambridge, Cambridge, UK. 8 Newborn Research Centre and Neonatal Services, The Royal Women’s Hospital, Melbourne,
Australia. 9 Murdoch Childrens Research Institute, Melbourne, Australia. 10 Department of Obstetrics and Gynecology, University of
Melbourne, Melbourne, Australia
Contact address: Claus Klingenberg, Department of Pediatrics, University Hospital of North Norway, Tromsø, N-9038, Norway.
claus.klingenberg@unn.no.
Citation: Klingenberg C, Wheeler KI, McCallion N, Morley CJ, Davis PG. Volume-targeted versus pressure-limited ventilation in
neonates. Cochrane Database of Systematic Reviews 2017, Issue 10. Art. No.: CD003666. DOI: 10.1002/14651858.CD003666.pub4.
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ABSTRACT
Background
Damage caused by lung overdistension (volutrauma) has been implicated in the development of bronchopulmonary dysplasia (BPD).
Modern neonatal ventilation modes can target a set tidal volume as an alternative to traditional pressure-limited ventilation (PLV)
using a fixed inflation pressure. Volume-targeted ventilation (VTV) aims to produce a more stable tidal volume in order to reduce lung
damage and stabilise the partial pressure of carbon dioxide (pCO2 ).
Objectives
To determine whether VTV compared with PLV leads to reduced rates of death and death or BPD in newborn infants and to determine
whether use of VTV affected outcomes including air leak, cranial ultrasound findings and neurodevelopment.
Search methods
We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL
2016, Issue 12), MEDLINE via PubMed (1966 to 13 January 2017), Embase (1980 to 13 January 2017) and CINAHL (1982 to
13 January 2017). We also searched clinical trials databases, conference proceedings and the reference lists of retrieved articles for
randomised controlled trials and quasi-randomised trials. We contacted the principal investigators of studies to obtain supplementary
information.
Selection criteria
Randomised and quasi-randomised trials comparing VTV versus PLV in infants of less than 44 weeks’ postmenstrual age and reporting
clinically relevant outcomes.
Volume-targeted versus pressure-limited ventilation in neonates (Review) 1
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Data collection and analysis
We assessed risk of bias for each trial using Cochrane methodology. We evaluated quality of evidence for each outcome using GRADE
criteria. We tabulated mortality, rates of BPD, short-term clinical outcomes and long-term developmental outcomes.
Statistics: for categorical outcomes, we calculated typical estimates for risk ratios (RR), risk differences (RD) and number needed to treat
for an additional beneficial outcome (NNTB). For continuous variables, we calculated typical estimates for mean differences (MD).
We used 95% confidence intervals (CI) and assumed a fixed-effect model for meta-analysis.
Main results
Twenty randomised trials met our inclusion criteria; 16 parallel trials (977 infants) and four cross-over trials (88 infants). No studies
were blinded and the quality of evidence for outcomes assessed varied from moderate to low.
We found no difference in the primary outcome, death before hospital discharge, between VTV modes versus PLV modes (typical RR
0.75, 95% CI 0.53 to 1.07; low quality evidence). However, there was moderate quality evidence that the use of VTV modes resulted
in a reduction in the primary outcome, death or BPD at 36 weeks’ gestation (typical RR 0.73, 95% CI 0.59 to 0.89; typical NNTB
8, 95% CI 5 to 20) and the following secondary outcomes: rates of pneumothorax (typical RR 0.52, 95% CI 0.31 to 0.87; typical
NNTB 20, 95% CI 11 to 100), mean days of mechanical ventilation (MD -1.35 days, 95% CI -1.83 to -0.86), rates of hypocarbia
(typical RR 0.49, 95% CI 0.33 to 0.72; typical NNTB 3, 95% CI 2 to 5), rates of grade 3 or 4 intraventricular haemorrhage (typical
RR 0.53, 95% CI 0.37 to 0.77; typical NNTB 11, 95% CI 7 to 25) and the combined outcome of periventricular leukomalacia with
or without grade 3 or 4 intraventricular haemorrhage (typical RR 0.47, 95% CI 0.27 to 0.80; typical NNTB 11, 95% CI 7 to 33).
VTV modes were not associated with any increased adverse outcomes.
Authors’ conclusions
Infants ventilated using VTV modes had reduced rates of death or BPD, pneumothoraces, hypocarbia, severe cranial ultrasound
pathologies and duration of ventilation compared with infants ventilated using PLV modes. Further studies are needed to identify
whether VTV modes improve neurodevelopmental outcomes and to compare and refine VTV strategies.
A comparison of volume-targeted ventilation modes with traditional pressure-limited ventilation modes for newborn babies
Review question: Does ventilator therapy of infants using a strategy targeting inflation volume rather than inflation pressure lead to
lower rates of death or lung damage (or both) among these infants?
Background: Preterm babies may need help to breathe. The risk of lung problems increases with increasing immaturity (the earlier
the babies are born). For some babies, the assistance of a ventilator (breathing machine) can be life saving; however, ventilators may
also injure the infant’s immature lungs. Traditionally, ventilators for infants have been used in a pressure-limited mode of ventilation,
where the pressure leads to variable amount of air entering the lungs. New volume-targeted methods of ventilation have been developed
which aim to reduce lung injury by controlling the amount of air entering the lungs with each inflation.
Study characteristics: In a search updated to January 2017, review authors identified 20 studies for inclusion in the review. Sixteen
studies (977 infants) compared two separate groups of infants treated with a volume-targeted mode of ventilation compared with a
pressure-limited mode of ventilation. In four studies (84 infants), the infants were treated with both modes of ventilation in a cross-
over design (where infants had ventilation with one method and were then swapped over to the second method). Most of the studies
were of moderate to low quality and none of them were blinded to those who assessed therapy. The most important results from this
review were based on data from eight to 12 studies including 584 to 771 infants.
Key results: Babies ventilated using volume-targeted modes of ventilation were more likely to survive free of lung damage. They needed
ventilator assistance for a shorter duration and were less likely to develop pneumothorax (a condition when air escapes from the lung
into the chest). They had more stable carbon dioxide levels in the blood, and had fewer brain ultrasound abnormalities. There was no
evidence that volume-targeted modes were more likely to harm the infant than traditional pressure-limited modes. More research is
needed to understand whether volume-targeted modes also lead to improvements in the development of movement and intellect. More
research is also needed comparing different volume-targeting techniques.
Volume-targeted versus pressure-limited ventilation in neonates (Review) 2
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Quality of evidence: Low to moderate quality as none of the studies were blinded and there were issues with study design in some of
the studies.
Outcomes Anticipated absolute effects* (95% CI) Relative effect No of participants Quality of the evidence Comments
(95% CI) (studies) (GRADE)
Death or BPD (36 Study population RR 0.73 584 ⊕⊕⊕
Unblinded studies.
weeks) (0.59 to 0.89) (8 RCTs) M oderate
458 per 1000 334 per 1000
(270 to 408)
Duration of positive M D of positive pressure M D 1.35 lower - 736 ⊕⊕⊕
Unblinded studies.
pressure ventilation ventilation (days); PLV (1.83 lower to 0.86 (12 RCTs) M oderate
(days) group 0 lower) in VTV group
Pneumothorax Study population RR 0.52 (0.31 to 0.87) 825 ⊕⊕⊕
Unblinded studies.
(13 RCTs) M oderate
88 per 1000 46 per 1000
(27 to 77)
IVH grade 3- 4 or PVL Study population RR 0.47 441 ⊕⊕⊕
Unblinded studies.
(0.27 to 0.80) (6 RCTs) M oderate
164 per 1000 77 per 1000
(44 to 131)
BPD (supplem ental Study population RR 0.68 (0.53 to 0.87) 620 ⊕⊕
Unblinded studies. Pos-
oxygen at 36 weeks) (9 RCTs) Low sible publication bias
346 per 1000 235 per 1000 based on f unnel plot
(183 to 301)
* The risk in the intervention group (and its 95% conf idence interval) is based on the assum ed risk in the com parison group and the relative effect of the intervention (and its
95% CI).
BPD: bronchopulm onary dysplasia; CI: conf idence interval; IVH: intraventricular haem orrhage; M D: m ean dif f erence; PLV: pressure-lim ited ventilation; PVL: periventricular
leukom alacia; RCT: random ised controlled trial; RR: risk ratio; VTV: volum e-targeted ventilation.
Figure 2. Risk of bias graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies.
Subgroup analyses
We reported subgroup analysis in infants weighing less than 1000
g, where possible, alongside the results for primary and secondary
outcomes.
Outcomes Anticipated absolute effects* (95% CI) Relative effect No of participants Quality of the evidence Comments
(95% CI) (studies) (GRADE)
Death or BPD (28 days) Study population RR 0.87 (0.64 to 1.18) 149 ⊕⊕
Unblinded studies. Im -
(3 RCTs) Low precision of estim ates,
536 per 1000 467 per 1000 95% CI < 0.75. Few par-
(343 to 633) ticipants
Failure of mode of ven- Study population RR 0.69 445 ⊕⊕⊕
Unblinded studies.
tilation (0.48 to 1.00) (5 RCTs) M oderate
242 per 1000 167 per 1000
(116 to 242)
Duration of positive The m ean duration of M D 0.08 lower - 381 ⊕⊕
Unblinded studies. Het-
pressure ventilation IPPV (log data) was 0 (0.16 lower to 0) (5 RCTs) Low erogeneity of study re-
(log data) sults.
Inspired oxygen con- The m ean dif f erence The m ean inspired oxy- - 324 ⊕⊕⊕
Unblinded studies.
centration %(study def - in inspired oxygen con- gen concentration % (7 RCTs) M oderate
inition) centration %; was 0.92 lower (2.08
PLV group 0 lower to 0.24 higher) in
VTV group
22
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Volume-targeted versus pressure-limited ventilation in neonates (Review)
Patent ductus arterio- Study population RR 0.95 754 ⊕⊕
Unblinded studies. Vari-
sus (0.80 to 1.12) (10 RCTs) Low able diagnostic prac-
391 per 1000 371 per 1000 tices em ployed.
(313 to 438)
Any IVH or PVL Study population RR 0.83 298 ⊕⊕⊕
Unblinded studies.
(0.58 to 1.18) (3 RCTs) M oderate
308 per 1000 256 per 1000
(179 to 364)
* The risk in the intervention group (and its 95% conf idence interval) is based on the assum ed risk in the com parison group and the relative effect of the intervention (and its
95% CI).
BPD: bronchopulm onary dysplasia; CI: conf idence interval; IPPV: interm ittent positive pressure ventilation; IVH: intraventricular haem orrhage; M D: m ean dif f erence; pCO2 :
partial pressure of carbon dioxide; PLV: pressure-lim ited ventilation; PVL: periventricular leukom alacia; RCT: random ised controlled trial; RR: risk ratio; VTV: volum e-targeted
ventilation.
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j.jpeds.2006.01.044; PUBMED: 16939738
Keszler 2004a {published and unpublished data} Swamy R, Gupta S, Singh J, Donn SM, Sinha SK. Tidal
Keszler M, Abubakar K. Volume guarantee: stability volume delivery and peak inspiratory pressure in babies
of tidal volume and incidence of hypocarbia. Pediatric receiving volume targeted or time cycled, pressure limited
Pulmonology 2004;38(3):240–5. DOI: 10.1002/ ventilation: a randomized controlled trial. Journal of
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ventilation on lung inflammatory response in preterm limited ventilation in preterm infants with respiratory
infants with respiratory distress syndrome (RDS). distress syndrome. Archives of Disease in Childhood. Fetal
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and Neonatal Edition 1997;77(3):F202–5. PUBMED: support ventilation reduces the risk of barotrauma in
9462190 ] premature children with severe respiratory syndrome. Acta
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Emergency Medicine 2007;16(7):703–5. resuscitation of preterm infants with controlled volume of
air/oxygen. clinicaltrials.gov/show/NCT00157989 Date
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NCT00295230 {published and unpublished data}
Abd El-Moneim 2005 {published data only}
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Abd El-Moneim ES, Fuerste HO, Krueger M, Elmagd
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NCT00295230 Date first received: 21 February 2006.
synchronized intermittent mandatory ventilation: a pilot
crossover trial in premature infants in their weaning phase. Olsen 2002 {published data only}
Pediatric Critical Care Medicine 2005;6(3):286–92. DOI: Olsen SL, Thibeault DW, Truog WE. Crossover trial
10.1097/01.PCC.0000161071.47031.61; PUBMED: comparing pressure support with synchronized intermittent
15857526 ventilation. Journal of Perinatology 2002;22(6):461–6.
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Abubakar 2001 {published data only}
Abubakar KM, Keszler M. Patient-ventilator interactions Ramirez-Del Valle 2006 {published data only}
in new modes of patient-triggered ventilation. Pediatric Ramirez-Del Valle JO, Villa-Guillen M, Reyes A, Murguia-
Pulmonology 2001;32(1):71–5. PUBMED: 11416879] de Sierra T. Tidal volume (VT ) delivery and stability
of different ventilatory parameters during synchronized
Abubakar 2006 {published data only}
mechanical ventilation with or without volume guarantee
Abubakar KM, Montazami S, Keszler M. Volume guarantee
(VG). Is VT stability always associated to peak inspiratory
accelerates recovery from endotracheal tube suctioning in
changes?. Pediatric Academic Societies Annual Meeting;
ventilated preterm infants. Pediatric Academic Societies
2006 April 29-May 2; San Francisco (CA). 2006.
Annual Meeting; 2006 April 29-May 2; San Francisco (CA)
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Shah 2013 {published data only}
Cheema 2001 {published data only}
Shah S, Kaul A. Volume targeted ventilation and arterial
Cheema IU, Ahluwahlia JS. Feasibility of tidal volume-
carbon dioxide in extremely preterm infants. Journal of
guided ventilation in newborn infants: a randomised
Neonatal and Perinatal Medicine 2013;6(4):339–44. DOI:
crossover trial using the volume guarantee modality.
10.3233/NPM-1372713
Pediatrics 2001;107(6):1323–8. PUBMED: 11389251]
Sinha 2008 {published data only}
Colnaghi 2006 {published data only} Sinha AK, Kempley ST. A randomised trial comparing
Colnaghi M, Weissmann G, Ciralli F, Matassa PG, Condo the effects of volume guided ventilation and synchronised
V, Messina D, et al. Volume-targeted ventilation and lung intermittent positive pressure ventilation on the cerebral and
inflammatory injury in preterm infants with RDS. Pediatric mesenteric circulation following surfactant administration.
Academic Societies Annual Meeting; 2006 April 29-May 2; 2nd Congress of the European Academy of Paediatrics;
San Francisco (CA) 2006. E–PAS2006:5506.340] 2008 Oct 24-28; Nice (France). 2008.
Dotta 2004 {published data only} Stefanescu 2015 {published data only}
Dotta A, Crescenzi F, Braguglia A, Campi F, Rechichi J, Stefanescu BM, Frewan N, Slaughter JC, O’Shea TM.
Orzalesi M. Cerebral haemodynamics in preterm infants Volume guarantee pressure support ventilation in extremely
during synchronized intermittent mandatory ventilation preterm infants and neurodevelopmental outcome at 18
(SIMV) and synchronized intermittent positive pressure months. Journal of Perinatology 2015;35(6):419–23. DOI:
ventilation (SIPPV), with and without volume guarantee 10.1038/jp.2014.228; PUBMED: 25569681
(VG). Pediatric Academic Societies’ Annual Meeting; 2004
Unal 2014 {unpublished data only}
May 1-4; San Francisco (CA). 2004. PAS2004:3061] Unal S, Ergenekon E, Aktas S, Altuntas N, Beken S, Kazanci
Keszler 2004b {published data only} E, et al. Evaluation of ventilatory parameters, short and
Keszler M, Abubakar KM. Volume guarantee accelerates long term morbidities in preterms ventilated with either
recovery from forced exhalation episodes. Pediatric PSV+VG or SIMV+VG. 5th Congress of the European
Academic Societies’ Annual Meeting; 2004 May 1-4, 2004; Academy of Paediatric Societies; 2014 Oct 17-21 October;
San Francisco (CA). 2004. PAS2004:3092] Barcelona (Spain) 2014. NCT01514331]
Lista 2000 {published data only} Wach 2003 {published data only}
Lista G, Marangione P, Azzali A, Castoldi F, Pogliani L, Wach RA, Osiovich HC. Can assist control plus volume
Compagnoni G. The “guaranteed volume” in pressure guarantee (AC+VG) avoid large tidal volumes (TV) in
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ventilated spontaneously breathing infants with BPD?. Bjorklund 1997
Pediatric Academic Societies’ Annual Meeting; 2003 May Bjorklund LJ, Ingimarsson J, Curstedt T, John J, Robertson
3-6; Seattle (Washington). 2003. PAS2003:2896] B, Werner O, et al. Manual ventilation with a few large
breaths at birth compromises the therapeutic effect of
References to studies awaiting assessment subsequent surfactant replacement in immature lambs.
Pediatric Research 1997;42(3):348–55. DOI: 10.1203/
Liu 2016 {unpublished data only} 00006450-199709000-00016; PUBMED: 9284276
Liu CZ, Huang BY, Tan BY, Guan HF, Xu XH, Guo QY.
Cannon 2000
Efficacy of volume-targeted ventilation for the treatment of
Cannon ML, Cornell J, Tripp-Hamel DS, Gentile MA,
neonatal respiratory distress syndrome. Zhongguo Dang Dai
Hubble CL, Meliones JN, et al. Tidal volumes for ventilated
Er Ke za Zhi [Chinese Journal of Contemporary Pediatrics]
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Miracle 2016 {published data only} of Respiratory and Critical Care Medicine 2000;162
Miracle X, Salvia MD, Figueras J, Rodriguez JM, (6):2109–12. DOI: 10.1164/ajrccm.162.6.9906112;
Carbonell X. Effects of pressure support plus volume PUBMED: 11112123
guarantee ventilation versus synchronized intermittent Chowdhury 2012
mandatory ventilation in extremely low birth weight Chowdhury O, Rafferty GF, Lee S, Hannam S, Milner
infants with respiratory distress syndrome: a prospective, AD, Greenough A. Volume-targeted ventilation in infants
randomized study. Journal of Maternal-Fetal and Neonatal born at or near term. Archives of Diseases in Childhood Fetal
Medicine 2016;29(Supple 1):236–7. DOI: 10.1080/ and Neonatal Edition 2012;97:F264.266. DOI: 10.1136/
14767058.2016.1191212; PUBMED: 27633796 archdischild-2011-301041; PUBMED: 22194469
References to ongoing studies Clark 2000
Clark RH, Slutsky AS, Gerstmann DR. Lung protective
ACTRN12609000986279 {unpublished data only} strategies of ventilation in the neonate: what are they?.
ACTRN12609000986279. A randomized controlled Pediatrics 2000;105(1 Pt 1):112–4. [PUBMED: 10617711]
trial of modes of ventilatory support in preterm babies Coalson 1999
from point of delivery to the neonatal intensive care unit. Coalson JJ, Winter VT, Siler-Khodr T, Yoder BA.
www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id= Neonatal chronic lung disease in extremely immature
308342&isReview=true Date first received: 9 July 2009. baboons. American Journal of Respiratory and Critical
Salvia 2006 {published and unpublished data} Care Medicine 1999;160(4):1333–46. DOI: 10.1164/
Salvia MD, Figueras J, Miracle X, Rodríguez-Miguélez ajrccm.160.4.9810071; PUBMED: 10508826
JM, Carbonell X. Effect of volume guarantee combined Dreyfuss 1993
with synchronized intermittent mandatory ventilation vs Dreyfuss D, Saumon G. Role of tidal volume, FRC and
synchronized intermittent mandatory ventilation in the end-inspiratory volume in the development of pulmonary
extremely premature. European Journal of Pediatrics 2006; edema following mechanical ventilation. American Review of
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Bhat 2016
Participants 40 infants.
Inclusion criteria: ≥ 34 weeks of GA and mechanically ventilated < 24 h in the first 2
weeks of life
Exclusion criteria: > 2 weeks of age, ventilated > 24 h with or without supported by high-
frequency ventilation or diagnosed with congenital diaphragmatic hernia
Interventions Ventilator: SLE5000 (software 4.3). Both groups initially: inflation time 0.3-0.4 sec,
inflation rate 40-60/min, PEEP not reported
• VTV group (n = 20): non-synchronised mode. Set inflation VTtarget 5 mL/kg.
Pmax set 5 cmH2 O above PIP used during previous conventional ventilation mode to
allow a VT delivery of 5 mL/kg.
• PLV group (n = 20): non-synchronised mode. PIP adjusted to achieve PaCO2
levels 4.5-7 kPa and pH > 7.25.
Both groups: predefined weaning strategy either VTV mode or PLV mode. Not men-
tioned whether synchronisation used during weaning
Duration of intervention: until extubation.
Notes
Risk of bias
Random sequence generation (selection Low risk Random number table generation (unspecified).
bias)
Allocation concealment (selection bias) Low risk Blinding of randomisation: sequential sealed opaque
envelopes
Incomplete outcome data (attrition bias) Low risk Follow-up: complete to end of intervention. Sec-
All outcomes ondary postintervention outcomes reported during
period of primary admission
Selective reporting (reporting bias) Unclear risk Trial registration submitted after completion of the
study.
Cheema 2007
Participants 40 infants.
Inclusion criteria: GA < 34 weeks and ventilated for RDS.
Exclusion criteria: major surgical or congenital anomalies.
Interventions Ventilator: both groups used Drager Babylog 8000plus in SIPPV (AC) mode
• VTV group (n = 19): SIPPV (AC) + VG. Set expired VTtarget 4.0 mL/kg. Pmax
described as “a balance between enabling the ventilator to deliver the desired tidal
volume and preventing excessive PIP.”
• PLV group (n = 21): SIPPV (AC). PIP determined by clinical team.
Duration of intervention: from onset of mechanical ventilation after admission to neona-
tal unit to first blood gas result (median duration 95 min)
Outcomes Data only collected from time between onset of ventilation and until first blood gas
analysis
Primary: PaCO2 and proportion of infants with PaCO2 within target range (5-7 kPa).
Others: first pH, PaO2.
Post hoc subgroup analysis 23-25, 26-33 weeks.
Supplemental data Blood gas data and data on randomisation procedure. Information about trial registration
Notes
Risk of bias
Random sequence generation (selection Low risk Permuted blocks within strata (< 1250 g and > 1250 g
bias) blocks)
Allocation concealment (selection bias) Low risk Blinding of randomisation: sealed envelopes.
Blinding of outcome assessment (detection High risk No (outcome measure defined end of intervention pe-
bias) riod).
All outcomes
Incomplete outcome data (attrition bias) Low risk Follow-up complete to discharge.
All outcomes
Chowdhury 2013
Participants 40 infants.
Inclusion criteria: < 34 weeks GA, mechanically ventilated in the first week after birth
Exclusion criteria: major congenital anomalies, ventilated > 24 h or supported by high-
frequency ventilation or both
Interventions Ventilator: SLE5000 (software 4,3). Both groups: inflation time 0.3-0.4 sec, inflation
rate 40-60/min, PEEP not reported
• VTV group (n = 20): SIMV + TTV at 5 mL/kg.
• PLV group (n = 20): SIMV.
Both groups: predefined weaning strategy; underlying trigger mode changed from SIMV
to AC
Duration of intervention: until extubation.
Supplemental data Mortality, BPD at 36 weeks, detailed blood gas, duration of ventilation presented as
mean (SD)
Notes Imbalance with regard to BW, GA and antenatal steroid use despite randomisation
Participants in the PLV group had lower median GA/BW than participants in the VTV
group (median GA/BW 26 weeks/856 g vs 28 weeks/1016 g). In the published report,
authors adjusted for this difference, but this review used the unadjusted outcomes
Risk of bias
Random sequence generation (selection Low risk Random number table generation.
bias)
Allocation concealment (selection bias) Low risk Blinding of randomisation: sealed opaque envelopes.
Incomplete outcome data (attrition bias) Low risk Follow-up: complete to end of intervention. Sec-
All outcomes ondary postintervention outcomes reported during
period of primary admission
Selective reporting (reporting bias) Unclear risk Trial registration submitted after completion of study.
Other bias High risk Despite randomisation, there was imbalance with re-
gard to BW, GA and antenatal steroid use. Participants
in the PLV group had lower median GA/BW than
participants in the VTV group (median GA/BW 26
weeks/856 g vs 28 weeks/1016 g)
D’Angio 2005
Participants 213 infants enrolled, but 1 infant immediately withdrawn, see below. Data on 212 infants
Inclusion criteria: BW 500-1249 g, GA ≥ 24 weeks and in need of mechanical ventilation.
Enrolled before 6 h of age
Exclusion criteria: not specified.
Interventions Ventilator: both groups used primarily the Siemens Servo 300 ventilator. However, par-
ticipants in the SIMV group were changed over to a VIP Bird ventilator (SIMV mode)
if requiring a ventilator rate > 40/min
Target: PaO2 (mmHg): 45-60 (GA 24-26 weeks), 50-70 (GA 27-28 weeks), 60-80 (GA
> 28 weeks). PaCO2 : 45-55 mmHg (all GAs).
• VTV group (n = 104): synchronised, pressure-limited AC mode (PRVC).
Supplemental data BW, age of death in non-survivors, BPD, duration of ventilation, pneumothorax, PIE,
PVL, IVH
Information regarding blinding of assessors. Study protocol.
Notes 1 infant in VTV group enrolled in error and immediately withdrawn from study. No
data collected on this participant. As such, study reported data on 212 infants; 104 in
the VTV group and 108 in the PLV group
Risk of bias
Random sequence generation (selection Low risk Block randomisation (8 participants per block). Strati-
bias) fied by centre and BW
Allocation concealment (selection bias) Low risk Blinding of randomisation: Sealed, opaque envelopes.
Intervention bias (strict vs hybrid studies) High risk Hybrid study: different trigger modes in VTV and PLV
groups.
Incomplete outcome data (attrition bias) Low risk Follow-up: complete to discharge.
All outcomes Long-term follow-up: 64 infants in each group were
also assessed at 6-18 months’ corrected age (neurode-
velopmental outcome)
Selective reporting (reporting bias) Unclear risk Study protocol sent to review authors. Study not regis-
tered.
Duman 2012
Participants 45 infants.
Inclusion criteria: GA < 32 weeks and mechanical ventilation for severe RDS for > 24 h
Exclusion criteria: major congenital anomalies and mechanical ventilation < 24 h
Interventions Ventilator: both groups used Drager Babylog 8000plus. Initially in SIPPV(AC) mode
and then switched to SIMV mode during weaning. Inflation time 0.3-0.4 sec and PEEP
4-6 cmH2 O. During weaning, respiratory rate was gradually reduced to 18/min. Clear
protocol for ventilation and weaning
Target: PaCO2 40-60 mmHg.
• VTV group (n = 23): SIPPV(AC) + VG and SIMV + VG. Set expired VTtarget 4
mL/kg. Pmax set 15-20% above mean PIP used to achieve VT. Adjustments done with
VT increments/decrements of 0.5 mL/kg.
• PLV group (n = 22): SIPPV(AC) and SIMV. PIP adjustments in increments/
decrements of 1-2 cmH2 O.
Duration of intervention: until extubation.
Supplemental data Duration of ventilation (mean and SD), clarification about the randomisation process
and inclusions/exclusions
Notes
Risk of bias
Random sequence generation (selection Low risk Block randomisation with random block sizes.
bias)
Allocation concealment (selection bias) Low risk Blinding of randomisation: sealed opaque envelopes.
Incomplete outcome data (attrition bias) Low risk Follow-up: complete to end of intervention. Sec-
All outcomes ondary postintervention outcomes reported during
period of primary admission
Erdemir 2014
Participants 60 infants.
Inclusion criteria: GA < 33 weeks or BW < 1500 g (or both); ventilated for RDS
Exclusion criteria: admission at > 6 h of age; congenital cardiac, respiratory or CNS
malformations; congenital metabolic diseases, congenital pneumonia, sepsis, perinatal
asphyxia and leak < 20% around the ETT
Supplemental data
Notes Initial ventilation with SIPPV, before start of weaning, lasted 7.8 h in PLV group and 4.
4 h in VTV group
Weaning phase lasted 32.4 h in PLV group and 21.1 h in VTV group. Intervention
mode consisted of 80% of total duration of ventilation in PLV group and 83% of total
duration of ventilation in VTV group
Risk of bias
Random sequence generation (selection Unclear risk Randomisation strategy not described.
bias)
Allocation concealment (selection bias) Low risk Blinding of randomisation: sealed opaque envelopes
Intervention bias (strict vs hybrid studies) High risk Hybrid study: different modes of flow termination. In
PSV mode, inflation times varies (flow termination).
In SIMV, there is a fixed inflation time
Guven 2013
Participants 72 infants.
Inclusion criteria: GA < 32 weeks or BW < 1500 g (or both), and admitted with RDS
and given surfactant within first 2 h of life
Exclusion criteria: major congenital anomalies, perinatal asphyxia and meconium aspi-
ration
Interventions Ventilator: both groups used Drager Babylog 8000plus in SIMV mode
• VTV group (n = 42): SIMV + VG. Set expired VTtarget 4-5 mL/kg. Pmax set 10
cmH2 O above PIP used for conventional mode.
• PLV group (n = 30): SIMV. PIP manually set to achieve an expired VT of 4-5
mL/kg and targeting “adequate” blood gases.
Duration of intervention: until extubation.
Outcomes Primary outcome: duration of ventilation (days) and need of total oxygen supplementa-
tion
Secondary outcomes: survival to discharge, air leak, BPD (36 weeks), IVH grade 3 or 4,
PVL, PDA, ROP and NEC
Supplemental data Information about postrandomisation loss sought from authors, see “Other bias.”
Notes
Risk of bias
Random sequence generation (selection Low risk Block randomisation with random block sizes.
bias)
Incomplete outcome data (attrition bias) Low risk Follow-up: complete to end of intervention.
All outcomes
Other bias High risk Reported in paper that 90 participants were ran-
domised. However, postrandomisation 15 participants
were excluded in PLV group and 3 participants ex-
cluded in VTV group. After contact with authors, it
seemed that randomisation occurred before they had
considered exclusion criteria and before parents had
given consent
Herrera 2002
Participants 17 infants.
Inclusion criteria: appropriate for GA infants of 600-1200 g, ventilated for RDS, > 48
h of age and clinically stable
Exclusion criteria: congenital malformations, sepsis, pneumothorax, other air leak, meco-
nium aspiration and terminal state
Interventions Ventilator: both groups used Draeger Babylog 8000plus. Prestudy settings, SIMV rate
16/min, PIP 15 cmH2 O.
Cross-over study:
• VTV epoch: SIMV + VG. Set expired VTtarget 4.5 mL//kg. Pmax set 10 cmH2 O
above preventilation PIP.
• PLV epoch: SIMV.
Duration of intervention: 1 + 1 h.
Supplemental data
Notes Last 8 infants (of 17) randomised to an additional third VTV epoch of SIMV-VG 3.0
mL/kg. For meta-analysis, only SIMV-VG 4.5 mL/kg (9 infants) vs SIMV data of all 17
infants used
Risk of bias
Random sequence generation (selection Unclear risk Randomised, but no further information
bias) about randomisation procedure
Allocation concealment (selection bias) Low risk Blinding of randomisation: sealed en-
velopes.
Selective reporting (reporting bias) Unclear risk Study protocol was unavailable for review.
Hummler 2006
Participants 15 infants.
Inclusion criteria: infants ≤ 1500 g. Ventilator dependent with a ventilator rate ≥ 10/
min and having recurrent hypoxaemic episodes (study definition)
Interventions Ventilator: Stephanie infant ventilator. Pressure controlled SIMV prior to study
Target: SpO2 82-90%. Standardised protocols for FiO2 adjustment.
Cross-over study:
• VTV epoch: volume controlled-SIMV. Pmax limit up to 40 cmH2 O. Inspired
VTtarget set from prestudy VT (7.8 ± 1.4 mL/kg).
Outcomes Primary: time with SpO2 < lower limit of target range (80-92%).
Other: time with SpO2 above/within target range, incidence/duration/severity of de-
saturation episodes, FiO2 , number of FiO2 adjustment necessary to target SpO2 , VT,
compliance, resistance.
Supplemental data
Notes
Risk of bias
Random sequence generation (selection Unclear risk Randomised, but no further information
bias) about randomisation procedure
Allocation concealment (selection bias) Low risk Blinding of randomisation: sealed en-
velopes.
Selective reporting (reporting bias) Unclear risk Study protocol unavailable for review.
Jain 2016
Participants 24 infants.
Inclusion criteria: < 32 weeks’ GA receiving PLV > 20/min, ≥ 4 episodes of hypoxaemia
(SpO2 < 75%) in 8 h prior to study.
Exclusion criteria: major congenital abnormalities, inotropes, sepsis or air leak within
previous 72 h prior to study
Interventions Ventilator: AVEA, CareFusion. Infants remained on mode of ventilation set by clinical
team before study. Volume targeting was only difference between groups
Cross-over study:
• PLV epoch: SIMV with pressure support or AC.
• VTV epoch: SIMV with pressure support + VG or AC + VG. Target VT set to
match mean expired VT of mechanical inflations before study (while infants were on
PLV). PIP limit set 10 cmH2 O above the PIP provided during PLV before study, and
remained unchanged for 24 h.
Duration of intervention: 24 + 24 h.
Outcomes Primary outcomes: proportion of time spent with arterial SpO2 < 75%.
Secondary outcomes: number and characteristics of hypoxaemic episodes; FiO2 median
and IQR, VT and minute ventilation.
Notes
Risk of bias
Random sequence generation (selection Unclear risk Randomisation sequence: not specified.
bias)
Allocation concealment (selection bias) Unclear risk Blinding of randomisation: not specified.
Incomplete outcome data (attrition bias) Low risk Follow-up: complete to end of interven-
All outcomes tion.
Participants 18 infants.
Inclusion criteria: < 34 weeks’ GA, ventilated for RDS before 6 h of age.
Exclusion criteria: congenital cardiac, respiratory or CNS anomalies, paralysis or sedation
or ETT leak > 30%
Interventions Ventilator: both groups used Drager Babylog 8000 plus with set backup rate 40/min
Target: PaCO2 of 35-45 torr (mmHg).
• VTV group (n = 9): AC-VG. Set expired VTtarget 5 mL/kg, adjusted by 0.5 mL/
kg to maintain target PaCO2 .
• PLV group (n = 9): AC. PIP set to achieve 4-6 mL/kg expired VT, using PIP
changes of 1-2 cmH2 O to maintain target PaCO2 .
Duration of intervention: 72 h or until extubation.
Outcomes Blood gas results, pneumothorax, PIE, mortality, cranial ultrasound scan
Supplemental data BW, age of death in non-survivors, BPD, duration of ventilation, pneumothorax, PIE,
PVL, IVH, blood gas data
Risk of bias
Random sequence generation (selection Low risk Random number table used to randomise participants.
bias)
Allocation concealment (selection bias) Low risk Blinding of randomisation: sealed envelopes.
Selective reporting (reporting bias) Unclear risk Study protocol unavailable for review.
Participants 53 infants.
Inclusion criteria: 25-32 weeks’ GA, received ≥ 1 course of antenatal steroids, ventilated
for RDS in first 24 h, treated with surfactant within 3 h
Exclusion criteria: lethal anomalies, receiving muscle relaxants at entry, IVH grade ≥ 2,
actual or suspected sepsis
Interventions Ventilator: both groups used Draeger Babylog 8000plus with set backup rate 40/min,
PEEP 3.5-4 cmH2 O. Mean inflation time 0.4-0.5 sec (upper limit in PSV mode)
Target: FiO2 to maintain SpO2 90-96%, pH > 7.25, PaO2 50-75 mmHg, PaCO2 40-
65 mmHg.
• VTV group (n = 30): PSV + VG. Set expired VTtarget 5 mL/kg throughout study.
• PLV group (n = 23): PSV. PIP set manually to achieve expired VT of around 5
mL/kg, and PIP weaned to achieve blood gas targets.
Duration of intervention: until extubation.
Supplemental data BW, age of death in non-survivors, BPD, duration of ventilation, pneumothorax, PIE,
PVL, IVH, postrandomisation loss
Notes Mean GA in PLV group was 29 weeks and mean GA in VTV group was 28 weeks
Risk of bias
Random sequence generation (selection Low risk Random number sequencing, stratified by GA (25-28
bias) weeks and 29-32 weeks) and centre
Allocation concealment (selection bias) Unclear risk Blinding of randomisation: not specified.
Incomplete outcome data (attrition bias) Low risk Follow-up: complete to discharge.
All outcomes
Selective reporting (reporting bias) Unclear risk Study protocol not available for review.
Other bias High risk Imbalance in numbers between the PLV and VTV
groups. Postrandomisation, 7 infants excluded because
placental histology identified chorioamnionitis (supple-
mental data), which could have influenced the primary
outcome of this study. After postrandomisation exclu-
sions, data from 30 infants in VTV group and 23 in-
fants in PLV group were reported
In post hoc subgroup of infants weighing < 1000 g
identified from supplemental data, 12/30 (40%) par-
ticipants in VTV group were < 1000 g compared with
5/23 (22%) in PLV group
Liu 2011
Participants 84 infants allocated to 3 ventilation groups: VTV (n = 31), PLV (n = 30) and high-
frequency ventilation (n = 23)
Only data from the 61 infants ventilated with PLV and VTV are included in meta-
analysis
Inclusion criteria: neonatal RDS, defined blood gas/oxygenation criteria, age < 12 h,
consent to surfactant
Exclusion criteria: congenital respiratory/cardiac malformations, pulmonary haemor-
rhage/gas leak/congenital pneumonia/meconium aspiration/wet lung/congenital heart
disease/IVH grade III-IV
Interventions Ventilator: Draeger Babylog 8000 (VTV group) and VIP Bird (PLV group)
• VTV group (n = 31): SIPPV-VG. Set expired VTtarget 4.0-6.0 mL/kg, rate 30-
40/min. Pmax limit: not described.
• PLV group (n = 30): IMV, PIP 20-25 cmH2 O, rate 30-40/min.
Duration of intervention: not stated.
Supplemental data Protocol and clarification on methods and results sought, but not received
Notes Denominators of outcomes beyond intervention periods were unclear due to challenges
following up participants who had transferred to other hospitals or who were withdrawn
from active clinical management for financial reasons. Only outcomes which occurred
during intervention period were included in meta-analysis
Risk of bias
Random sequence generation (selection Unclear risk Random number table used, method not specified.
bias) Unequal allocation to 3 groups (PLV, VTV and high-
frequency ventilation), and overall substantially more
boys (n = 57) than girls (n = 27) included
Intervention bias (strict vs hybrid studies) High risk Hybrid study: different ventilators.
Incomplete outcome data (attrition bias) High risk Completeness of follow-up not stated.
All outcomes
Nafday 2005
Participants 34 infants.
Inclusion criteria: BW < 1500 g, clinical and radiographic RDS, < 12 h old, about to
receive surfactant
Exclusion criteria: major congenital malformations, congenital heart disease, confirmed/
suspected sepsis/pneumonia, pneumothorax, other air leak, requiring paralysis/heavy
sedation, moribund
Interventions Ventilator: both groups used Drager Babylog 8000plus. Ventilator rate adjusted to target
blood gas values
Target: pH 7.25-7.35, PaCO2 45-55 mmHg, PaO2 50-70 mmHg, SpO2 88-95%.
• VTV group (n = 16): PSV-VG. Set expired VTtarget 5 mL/kg.
• PLV group (n = 18): SIMV. Measured VT not used to adjust PIP during
intervention.
Duration of intervention: 24 h.
Outcomes Primary: ventilatory pressures during first 24 h after surfactant administration or ran-
domisation
Others: survival to discharge, BPD (36 weeks), IVH, PDA (requiring indomethacin or
ligation), NEC (Bell ≥ 2), air leak (PIE, pneumothorax, pneumomediastinum)
Notes
Risk of bias
Random sequence generation (selection Low risk Block randomisation, stratified by weight (500-750 g,
bias) 751-1000 g, 1001-1250 g, 1251-1500 g)
Allocation concealment (selection bias) Low risk Blinding of randomisation: sealed envelopes.
Intervention bias (strict vs hybrid studies) High risk Hybrid study: different modes of flow termination. In
PSV mode, inflation times varies (flow termination).
In SIMV, there is a fixed inflation time
Incomplete outcome data (attrition bias) Low risk Follow-up: complete to discharge.
All outcomes
Selective reporting (reporting bias) Unclear risk Study protocol unavailable for review.
Piotrowski 1997
Participants 57 infants.
Inclusion criteria: BW < 2500 g, postnatal age < 72 h, and need for mechanical ventilation
for lung disease at randomisation and Servo ventilator available
Exclusion criteria: sepsis/pneumonia, congenital malformation, pneumothorax or any
other air leak, meconium aspiration
Interventions Ventilator: different ventilators used for experimental group (Siemens Sevo 300 ventila-
tor) and control group (Bear Cub or Sechrist ventilator). Both groups ventilated using
PEEP 3-5 cmH2 O and inflation time 0.5 sec.
Target: SpO2 88-95%, pCO2 < 55 mmHg. Infants extubated once ventilator rate < 12/
min, FiO2 < 0.25, and after 30-60 min trial of ETT-CPAP.
• VTV group (n = 27): synchronised, pressure-limited AC mode (PRVC).
Outcomes Death in hospital, oxygen at 28 days, any air leak, pneumothorax, PIE, any IVH, IVH
grade 3-4, PDA, sepsis, use of muscle relaxants, duration of ventilation
Notes Mean GA in PLV group was 29 weeks and mean GA in VTV group was 30 weeks
Risk of bias
Random sequence generation (selection Unclear risk Randomised, but no further information about ran-
bias) domisation procedure
Allocation concealment (selection bias) Low risk Blinding of randomisation: sealed envelopes.
Intervention bias (strict vs hybrid studies) High risk Hybrid study; the VTV group and PLV group used
different ventilator models, modes and synchronisa-
tion settings
Selective reporting (reporting bias) Unclear risk Study protocol unavailable for review.
Participants 56 infants.
Inclusion criteria: GA 24-32 weeks with RDS, requiring ventilation for ≥ 24 h
Exclusion criteria: severe congenital malformation, lack of parental consent and pul-
monary air leak on admission
Interventions Ventilator: VTV group (PRVC) used Siemens Servo 300. PLV group (SIMV) used 1 of
the 4 different ventilators (depending on availability): Bear Cub (CEM)/Bear 750 PSV,
Sechrist Millenium, Draeger Babylog 8000 plus or SLE 5000
Both groups: inflation time 0.4 sec, inflation rate 40/min, PEEP 3-5 cmH2 O.
• VTV group (n = 30): synchronised, pressure-limited AC mode (PRVC).
Sequentially variation of the delivered PIP to approximate a target inspiratory VTtarget
8-10 mL/kg (included allowance for circuit compliance).
• PLV group (n = 26): SIMV.
Duration of intervention: until extubation.
Outcomes Primary outcome: ≥ 12 h with “effective ventilation” (SpO2 > 90 %, PaCO2 < 50
mmHg) with FiO2 < 0.23 and PIP < 15 cmH2 O.
Secondary outcomes: time to extubation, BPD (28 days), air leak, IVH and PDA
Supplemental data Results translated into English. Information regarding stratification sought
Notes Despite randomisation, there were imbalances between VTV and PLV groups in FiO2
in first 6 h of life and surfactant use (higher FiO2 and more surfactant used in the VTV
group). In published report, authors adjusted for this difference, but in this review the
unadjusted outcomes were used
Median GA in PLV group was 28 weeks and median GA in VTV group was 28 weeks
Risk of bias
Random sequence generation (selection Low risk Sequential numbers. Stratified by GA (24-28 weeks
bias) and 29-33 weeks)
Allocation concealment (selection bias) Low risk Blinding of randomisation: sealed envelopes.
Intervention bias (strict vs hybrid studies) High risk Hybrid study: different ventilators.
Incomplete outcome data (attrition bias) Low risk Follow-up: complete to discharge.
All outcomes
Selective reporting (reporting bias) Unclear risk Study protocol unavailable for review.
Other bias High risk Although randomised, infants in the VTV (PRVC)
group had increased surfactant use and increased FiO2
in first 6 h after admission.
Polimeni 2006
Participants 32 Infants.
Inclusion criteria: BW <1500 g, recovered from RDS, presenting with hypoxaemic
episodes
Notes
Risk of bias
Random sequence generation (selection Unclear risk Randomised, but no further information
bias) about randomisation procedure
Selective reporting (reporting bias) Low risk Study protocol sent to review authors.
Study retrospectively registered
Singh 2006
Outcomes Primary outcome criteria: time from entry into the study until achievement of either
AaDO2 < 13 kPa for > 12 h or MAP < 8.0 cmH2 O for > 12 h.
Other: total duration of mechanical ventilation, duration of MV + CPAP, survival to
discharge, frequency of complications: BPD (36 weeks), IVH, PVL, PDA (requiring
treatment), NEC (Bell grade ≥ 2), FiO2 (data from Swamy 2008).
Follow-up (Singh 2009): need for home oxygen, cough, wheeze, inhaler use, rate of
hospital readmission, rate of respiratory readmission, neurodisability (cerebral palsy, deaf,
behavioural problems, blindness) by questionnaire
Supplemental data BW, age of death in non-survivors, BPD, duration of ventilation, pneumothorax, PIE,
PVL, IVH, PDA
Notes 109 infants enrolled in Singh 2006, of whom 94 survived to discharge. 3 infants died
post-discharge
Follow-up studies:
Singh 2009: 85/91 (93%) infants eligible for follow-up assessed at median of 22 months’
corrected age; 45 in VTV group and 40 in PLV group (Singh 2009). Reported on
pulmonary morbidities and gross neurodevelopmental outcomes and mortality
Swamy 2008: reported on respiratory parameters
Risk of bias
Random sequence generation (selection Low risk Random block randomisation. Stratified by BW.
bias)
Allocation concealment (selection bias) Low risk Blinding of randomisation: sealed, opaque envelopes.
Blinding of outcome assessment (detection High risk Blinding of outcome measurements to discharge: no.
bias) Investigators involved in long-term follow-up were
All outcomes blinded to original treatment modality
Incomplete outcome data (attrition bias) Low risk Follow-up: complete to discharge. 85/91 (93%) infants
All outcomes eligible for follow-up were assessed at a median of 22
months’ corrected age
Selective reporting (reporting bias) Unclear risk Study protocol unavailable for review.
Other bias Unclear risk Both arms weaned using PLV mode.
Sinha 1997
Participants 50 infants.
Inclusion criteria: BW > 1200 g and had RDS requiring mechanical ventilation
Exclusion criteria: confirmed/suspected sepsis/pneumonia, congenital malformation or
lack of arterial access
Interventions Ventilator: both groups used VIP Bird ventilator in AC mode with inflation time at 0.
3-0.5 sec
Target: pH 7.27-7.40, PaCO2 4.5 to 6 kPa, PaO2 8-11 kPa.
Outcomes “Success” criteria outcome: time from entry into study until achievement of either
AaDO2 < 13 kPa for > 12 h or MAP < 8.0 cmH2 O for > 12 h or extubation.
Other outcome criteria: death in hospital, failed allocated treatment, IVH or PVL (not
reported separately), BPD (in oxygen at 36 weeks), pneumothorax, PDA
Notes
Risk of bias
Random sequence generation (selection Unclear risk Randomised, but no further information about ran-
bias) domisation procedure
Allocation concealment (selection bias) Low risk Blinding of randomisation: sealed envelopes.
Blinding of outcome assessment (detection High risk Was done for chest x-ray findings, but not for other
bias) outcome
All outcomes
Intervention bias (strict vs hybrid studies) High risk Hybrid study: VTV mode was pressure triggered. PLV
mode was flow triggered
Selective reporting (reporting bias) Unclear risk Study protocol not available.
Other bias Unclear risk Both arms weaned using a PLV mode.
Participants 30 infants.
Inclusion criteria: very low BW (≤ 1500 g, ≤ 32 weeks GA) infants with hyaline mem-
brane disease
Exclusion criteria: perinatal infection, positive lower respiratory tract culture, blood in
ETT secretion or pulmonary haemorrhage, severe congenital malformation
Interventions Ventilator: both groups used Drager Babylog 8000plus in SIMV mode
• VTV group (n = 15): SIMV + VG. Set expired VTtarget 5.0 mL/kg. Pmax not
described.
• PLV group (n = 15): SIMV. PIP determined by clinical team.
Rest of ventilator parameters regulated according to blood gases analysis
Duration of intervention: not described.
Supplemental data Protocol and clarification on methods and results sought, but not received
Notes Denominators of outcomes beyond intervention periods were unclear due to challenges
following up participants who had transferred to other hospitals or who were withdrawn
from active clinical management for financial reasons. Only outcomes which occurred
during intervention period were included in meta-analysis
Risk of bias
Random sequence generation (selection Unclear risk Randomised, but no further information about ran-
bias) domisation procedure
Incomplete outcome data (attrition bias) High risk Postintervention outcomes report on 25/30 (83%)
All outcomes participants. Stated reasons included financial drop-
outs and withdrawal from study due to IVH
Selective reporting (reporting bias) Unclear risk Review authors requested study protocol, but received
no response
AaDO2 : alveolar to arterial oxygen pressure difference; AC: assist control; BPD: bronchopulmonary dysplasia; BW: birth weight; CPAP:
continuous positive airway pressure; CNS: central nervous system; ETT: endotracheal tube; FiO2 : fraction of inspired oxygen; GA:
gestational age; h: hour; IQR: interquartile range; IMV: intermittent mandatory ventilation; IVH: intraventricular haemorrhage;
MAP: mean airway pressure; min: minute; MV: mandatory ventilation; n: number of infants; NEC: necrotising enterocolitis; Pmax :
maximum peak inflation pressure; pCO2 : partial pressure of carbon dioxide; PaCO2 : partial pressure of carbon dioxide in arterial
blood; PaO2 : partial pressure of oxygen in arterial blood; PDA: patent ductus arteriosus; PEEP: positive end-expiratory pressure;
PIE: pulmonary interstitial emphysema; PIP: peak inflation pressure; PLV: pressure-limited ventilation; Pmax : maximum peak
inflation pressure; PRVC: pressure-regulated volume control; PSV: pressure support ventilation; PVL: periventricular leukomalacia;
RDS: respiratory distress syndrome; ROP: retinopathy of prematurity; SD: standard deviation; sec: second; SIMV: synchronised
intermittent mandatory ventilation; SIPPV: synchronised intermittent positive pressure ventilation (same as AC); SpO2 : blood
oxygen saturation level; TcCO2 : transcutaneous carbon dioxide; Timax : maximal inspiratory time; TTV: targeted tidal volume; VG:
volume guarantee; VTtarget : target tidal volume; VTV: volume-targeted ventilation.
Abd El-Moneim 2005 Journal publication. Cross-over study, but not randomised.
Abubakar 2001 Journal publication. Order of ventilatory modes not randomised in this cross-over study which means
that an effect of fatigue cannot be excluded. Additionally, study did not report outcomes specified in this
Cochrane Review
Abubakar 2006 Abstract presentation. Study investigating time to recovery after ETT suction in infants randomised to
ventilation with/without VG mode. Study did not report outcomes specified in this Cochrane Review
Cheema 2001 Journal publication. Short-term cross-over study did not address any of the outcomes of this Cochrane
Review. Also, the cross-over was made from PLV to VG mode without changing Pmax , which may have
interfered with the ventilator’s capacity to deliver the set VT and hence affected the outcomes
Colnaghi 2006 Abstract presentation. Randomised trial comparing 3 groups ventilated with Draeger Babylog 8000plus:
group 1: PSV; group 2: PSV + VG; group 3: AC + VG
However, outcomes were biochemical assays of inflammatory markers in serum and tracheal aspirates.
Study did not report outcomes specified in this Cochrane Review. Despite randomisation, there were
inception differences in study group characteristics
We attempted to contact authors for further information.
Dotta 2004 Abstract presentation. Randomised study, but authors did not report outcomes specified in this Cochrane
Review
Keszler 2004b Abstract presentation. Abstract did not report whether interventions randomised. Study outcomes did not
include those specified in this Cochrane Review
NCT00295230 Study designed to compare effects of VG with pressure supported vs synchronised intermittent mandatory
ventilation in very low birth weight infants. Study started in 2006, but later participant recruitment was
suspended due to suboptimal enrolment after 18 months, and study was terminated
Olsen 2002 Journal publication. Cross-over study that did not discuss outcome measurements of this Cochrane Review
Ramirez-Del Valle 2006 Abstract presentation. Randomised study, but authors did not report the outcomes specified in this
Cochrane Review
Sinha 2008 Abstract presentation. Outcomes did not include those specified in this Cochrane Review
Unal 2014 Abstract presentation. Comparing 2 VTV modes, no comparison with PLV mode
Wach 2003 Abstract presentation. No information in the abstract whether intervention was randomised. Outcomes
did not include those specified in this Cochrane Review
AC: assist control; ETT: endotracheal tube; Pmax : maximum peak inflation pressure; PLV: pressure-limited ventilation; PSV: pressure
support ventilation; VG: volume guarantee; VT: tidal volume; VTV: volume-targeted ventilation.
Liu 2016
Methods Article published in Chinese. We have not been able to obtain a translated version
Participants
Interventions
Outcomes
Outcomes
PSV: pressure support ventilation; SIMV: synchronised intermittent mandatory ventilation; VG: volume guarantee.
ACTRN12609000986279
Trial name or title A Randomised Controlled Trial of Modes of Ventilatory Support in Preterm Infants from Point of Delivery
to the Neonatal Intensive Care Unit
Outcomes PaCO2 , PaO2 , cerebral blood flow, IVH grade 3-4, PVL, BPD, neurodevelopmental impairment at 1 and 3
years
Salvia 2006
Trial name or title Effect of VG Combined with SIMV vs SIMV in the Extremely Premature Infant
Notes Studied from 30 min after first surfactant dose. Study is ongoing and collecting 2-year follow-up data.
Hitherto only short-term outcomes have been presented in abstract form. Longer-term follow-up is in progress
(information from author), and the final published data are awaited. We have attempted to contact the authors
for further information
BPD: bronchopulmonary dysplasia; FiO2 : fraction of inspired oxygen; IMV: intermittent mandatory ventilation; IVH: intraventricular
haemorrhage; MAP: mean airway pressure; PaCO2 : partial pressure of carbon dioxide in arterial blood; PaO2 : partial pressure
of oxygen in arterial blood; PDA: patent ductus arteriosus; PIP: peak inflation pressure; PLV: pressure-limited ventilation; PVL:
periventricular leukomalacia; SIMV: synchronised intermittent mandatory ventilation; SpO2 : blood oxygen saturation level; VG:
volume guarantee; VT: tidal volume; VTV: volume-targeted ventilation.
Comparison 1. Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by mode
of ventilation
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Death before discharge from 11 771 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.53, 1.07]
hospital
1.1 Strict studies 4 220 Risk Ratio (M-H, Fixed, 95% CI) 0.60 [0.31, 1.15]
1.2 Hybrid studies 7 551 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.55, 1.25]
2 Death or bronchopulmonary 8 584 Risk Ratio (M-H, Fixed, 95% CI) 0.73 [0.59, 0.89]
dysplasia (BPD) (36 weeks)
2.1 Strict studies 4 220 Risk Ratio (M-H, Fixed, 95% CI) 0.68 [0.50, 0.94]
2.2 Hybrid studies 4 364 Risk Ratio (M-H, Fixed, 95% CI) 0.76 [0.58, 0.99]
3 Failure of mode of ventilation 5 445 Risk Ratio (M-H, Fixed, 95% CI) 0.69 [0.48, 1.00]
3.1 Strict studies 2 149 Risk Ratio (M-H, Fixed, 95% CI) 0.87 [0.44, 1.72]
3.2 Hybrid studies 3 296 Risk Ratio (M-H, Fixed, 95% CI) 0.63 [0.40, 0.97]
4 Addition of neuromuscular 2 75 Risk Ratio (M-H, Fixed, 95% CI) 0.32 [0.07, 1.40]
paralysis where previously not
paralysed
4.1 Strict studies 1 18 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
4.2 Hybrid studies 1 57 Risk Ratio (M-H, Fixed, 95% CI) 0.32 [0.07, 1.40]
5 Duration of positive pressure 12 736 Mean Difference (IV, Fixed, 95% CI) -1.35 [-1.83, -0.86]
ventilation (days, survivors)
5.1 Strict studies 5 229 Mean Difference (IV, Fixed, 95% CI) -2.08 [-3.51, -0.64]
5.2 Hybrid studies 7 507 Mean Difference (IV, Fixed, 95% CI) -1.25 [-1.77, -0.74]
6 Duration of positive pressure 5 381 Mean Difference (IV, Fixed, 95% CI) -0.08 [-0.16, -0.00]
ventilation (log data, survivors)
6.1 Strict studies 3 152 Mean Difference (IV, Fixed, 95% CI) -0.14 [-0.24, -0.04]
6.2 Hybrid studies 2 229 Mean Difference (IV, Fixed, 95% CI) 0.02 [-0.12, 0.15]
7 Inspired oxygen concentration 7 324 Mean Difference (IV, Fixed, 95% CI) -0.92 [-2.08, 0.24]
% (study definition)
7.1 Parallel studies 3 156 Mean Difference (IV, Fixed, 95% CI) -1.42 [-3.09, 0.24]
7.2 Cross-over studies 4 168 Mean Difference (IV, Fixed, 95% CI) -0.44 [-2.05, 1.17]
8 Any pH < 7.25 3 98 Risk Ratio (M-H, Fixed, 95% CI) 0.80 [0.52, 1.23]
9 Hypocarbia partial pressure of 3 98 Risk Ratio (M-H, Fixed, 95% CI) 0.49 [0.33, 0.72]
carbon dioxide (pCO2 ) < 35
mmHg/4.7 kPa
10 Respiratory acidosis; pH < 7.25 3 98 Risk Ratio (M-H, Fixed, 95% CI) 0.93 [0.51, 1.70]
and pCO2 > 8 kPa
11 Incidence of hypocarbia or 2 58 Risk Ratio (M-H, Fixed, 95% CI) 0.69 [0.42, 1.12]
respiratory acidosis
12 Patent ductus arteriosus 10 754 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.80, 1.12]
12.1 Strict studies 3 202 Risk Ratio (M-H, Fixed, 95% CI) 0.81 [0.61, 1.08]
12.2 Hybrid studies 7 552 Risk Ratio (M-H, Fixed, 95% CI) 1.01 [0.83, 1.25]
13 Air leak (any) 5 374 Risk Ratio (M-H, Fixed, 95% CI) 0.79 [0.44, 1.43]
13.1 Strict studies 2 71 Risk Ratio (M-H, Fixed, 95% CI) 0.51 [0.09, 2.81]
13.2 Hybrid Studies 3 303 Risk Ratio (M-H, Fixed, 95% CI) 0.84 [0.45, 1.58]
Volume-targeted versus pressure-limited ventilation in neonates (Review) 60
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
14 Pneumothorax 13 825 Risk Ratio (M-H, Fixed, 95% CI) 0.52 [0.31, 0.87]
14.1 Strict studies 5 250 Risk Ratio (M-H, Fixed, 95% CI) 0.53 [0.19, 1.44]
14.2 Hybrid studies 8 575 Risk Ratio (M-H, Fixed, 95% CI) 0.52 [0.28, 0.94]
15 Pulmonary interstitial 6 430 Risk Ratio (M-H, Fixed, 95% CI) 1.21 [0.63, 2.30]
emphysema
15.1 Strict studies 2 71 Risk Ratio (M-H, Fixed, 95% CI) 0.77 [0.12, 5.04]
15.2 Hybrid studies 4 359 Risk Ratio (M-H, Fixed, 95% CI) 1.29 [0.64, 2.57]
16 Any intraventricular 6 501 Risk Ratio (M-H, Fixed, 95% CI) 0.90 [0.70, 1.15]
haemorrhage (IVH)
16.1 Strict studies 2 125 Risk Ratio (M-H, Fixed, 95% CI) 1.11 [0.74, 1.67]
16.2 Hybrid studies 4 376 Risk Ratio (M-H, Fixed, 95% CI) 0.82 [0.60, 1.11]
17 Periventricular leukomalacia 7 508 Risk Ratio (M-H, Fixed, 95% CI) 0.45 [0.21, 0.98]
(PVL)
17.1 Strict studies 4 218 Risk Ratio (M-H, Fixed, 95% CI) 0.53 [0.17, 1.65]
17.2 Hybrid studies 3 290 Risk Ratio (M-H, Fixed, 95% CI) 0.40 [0.14, 1.14]
18 IVH grade 3-4 10 712 Risk Difference (M-H, Fixed, 95% CI) -0.09 [-0.14, -0.04]
18.1 Strict studies 4 218 Risk Difference (M-H, Fixed, 95% CI) -0.05 [-0.13, 0.02]
18.2 Hybrid studies 6 494 Risk Difference (M-H, Fixed, 95% CI) -0.10 [-0.17, -0.04]
19 Any IVH or PVL 3 298 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.58, 1.18]
19.1 Strict studies 2 125 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.52, 1.35]
19.2 Hybrid studies 1 173 Risk Ratio (M-H, Fixed, 95% CI) 0.82 [0.48, 1.39]
20 IVH grade 3-4 or PVL 6 441 Risk Ratio (M-H, Fixed, 95% CI) 0.47 [0.27, 0.80]
20.1 Strict studies 4 218 Risk Ratio (M-H, Fixed, 95% CI) 0.51 [0.25, 1.03]
20.2 Hybrid studies 2 223 Risk Ratio (M-H, Fixed, 95% CI) 0.42 [0.19, 0.96]
21 BPD (supplemental oxygen in 9 620 Risk Ratio (M-H, Fixed, 95% CI) 0.68 [0.53, 0.87]
survivors at 36 weeks only)
21.1 Strict studies 4 218 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.52, 1.07]
21.2 Hybrid studies 5 402 Risk Ratio (M-H, Fixed, 95% CI) 0.64 [0.46, 0.89]
Comparison 2. Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants weighing
less than 1000 g
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Death in hospital 5 246 Risk Ratio (M-H, Fixed, 95% CI) 0.71 [0.42, 1.21]
1.1 Strict studies 4 226 Risk Ratio (M-H, Fixed, 95% CI) 0.80 [0.46, 1.39]
1.2 Hybrid studies 1 20 Risk Ratio (M-H, Fixed, 95% CI) 0.25 [0.03, 1.86]
2 Death or bronchopulmonary 4 224 Risk Ratio (M-H, Fixed, 95% CI) 0.79 [0.62, 1.01]
dysplasia (BPD) (36 weeks)
2.1 Strict studies 3 81 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.52, 1.10]
2.2 Hybrid studies 1 143 Risk Ratio (M-H, Fixed, 95% CI) 0.82 [0.59, 1.12]
3 Duration of positive pressure 5 198 Mean Difference (IV, Fixed, 95% CI) -0.82 [-4.43, 2.80]
ventilation (days, survivors)
3.1 Strict studies 3 63 Mean Difference (IV, Fixed, 95% CI) -0.32 [-4.53, 3.89]
3.2 Hybrid studies 2 135 Mean Difference (IV, Fixed, 95% CI) -2.21 [-9.29, 4.87]
4 Duration of positive pressure 5 198 Mean Difference (IV, Fixed, 95% CI) -0.01 [-0.12, 0.10]
ventilation (log data, survivors)
4.1 Strict studies 3 63 Mean Difference (IV, Fixed, 95% CI) -0.04 [-0.23, 0.14]
Volume-targeted versus pressure-limited ventilation in neonates (Review) 61
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
4.2 Hybrid studies 2 135 Mean Difference (IV, Fixed, 95% CI) 0.01 [-0.12, 0.14]
5 Any pH < 7.25 2 46 Risk Ratio (M-H, Fixed, 95% CI) 0.71 [0.46, 1.09]
6 Hypocarbia partial pressure of 1 6 Risk Ratio (M-H, Fixed, 95% CI) 0.19 [0.01, 2.36]
carbon dioxide (pCO2 ) < 35
mmHg/4.7 kPa
7 Respiratory acidosis pH < 7.25 2 46 Risk Ratio (M-H, Fixed, 95% CI) 0.79 [0.43, 1.47]
and pCO2 > 60 mmHg/8 kPa
8 Hypocarbia or respiratory 1 6 Risk Ratio (M-H, Fixed, 95% CI) 0.19 [0.01, 2.36]
acidosis
9 Patent ductus arteriosus 4 241 Risk Ratio (M-H, Fixed, 95% CI) 1.09 [0.85, 1.39]
9.1 Strict studies 2 75 Risk Ratio (M-H, Fixed, 95% CI) 1.10 [0.77, 1.57]
9.2 Hybrid studies 2 166 Risk Ratio (M-H, Fixed, 95% CI) 1.08 [0.78, 1.50]
10 Air leak (any) 4 189 Risk Ratio (M-H, Fixed, 95% CI) 1.11 [0.55, 2.23]
10.1 Strict studies 2 23 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.10, 7.24]
10.2 Hybrid studies 2 166 Risk Ratio (M-H, Fixed, 95% CI) 1.14 [0.54, 2.40]
11 Pneumothorax 5 247 Risk Ratio (M-H, Fixed, 95% CI) 0.63 [0.29, 1.37]
11.1 Strict studies 3 81 Risk Ratio (M-H, Fixed, 95% CI) 0.46 [0.11, 1.90]
11.2 Hybrid studies 2 166 Risk Ratio (M-H, Fixed, 95% CI) 0.72 [0.28, 1.86]
12 Pulmonary interstitial 4 189 Risk Ratio (M-H, Fixed, 95% CI) 1.45 [0.58, 3.67]
emphysema
12.1 Strict studies 2 23 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.10, 7.24]
12.2 Hybrid studies 2 166 Risk Ratio (M-H, Fixed, 95% CI) 1.62 [0.58, 4.53]
13 Any intraventricular 4 225 Risk Ratio (M-H, Fixed, 95% CI) 0.79 [0.55, 1.16]
haemorrhage (IVH)
13.1 Strict studies 2 62 Risk Ratio (M-H, Fixed, 95% CI) 1.14 [0.62, 2.08]
13.2 Hybrid studies 2 163 Risk Ratio (M-H, Fixed, 95% CI) 0.66 [0.40, 1.06]
14 IVH grade 3-4 4 184 Risk Ratio (M-H, Fixed, 95% CI) 0.53 [0.27, 1.04]
14.1 Strict studies 3 164 Risk Ratio (M-H, Fixed, 95% CI) 0.61 [0.28, 1.36]
14.2 Hybrid studies 1 20 Risk Ratio (M-H, Fixed, 95% CI) 0.33 [0.09, 1.27]
15 Periventricular leukomalacia 4 203 Risk Ratio (M-H, Fixed, 95% CI) 0.43 [0.15, 1.24]
(PVL)
15.1 Strict studies 3 79 Risk Ratio (M-H, Fixed, 95% CI) 0.38 [0.10, 1.53]
15.2 Hybrid studies 1 124 Risk Ratio (M-H, Fixed, 95% CI) 0.5 [0.10, 2.63]
16 Any IVH or PVL 3 186 Risk Ratio (M-H, Fixed, 95% CI) 0.90 [0.60, 1.35]
16.1 Strict studies 2 62 Risk Ratio (M-H, Fixed, 95% CI) 1.05 [0.61, 1.80]
16.2 Hybrid studies 1 124 Risk Ratio (M-H, Fixed, 95% CI) 0.78 [0.43, 1.42]
17 IVH grade 3-4 or PVL 3 145 Odds Ratio (M-H, Fixed, 95% CI) 0.39 [0.15, 0.99]
17.1 Strict studies 2 21 Odds Ratio (M-H, Fixed, 95% CI) 0.10 [0.01, 1.04]
17.2 Hybrid studies 1 124 Odds Ratio (M-H, Fixed, 95% CI) 0.56 [0.19, 1.64]
18 BPD (supplemental oxygen in 4 202 Risk Ratio (M-H, Fixed, 95% CI) 0.81 [0.59, 1.12]
survivors at 36 weeks)
18.1 Strict studies 3 79 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.49, 1.50]
18.2 Hybrid studies 1 123 Risk Ratio (M-H, Fixed, 95% CI) 0.79 [0.53, 1.18]
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Severe disability (any definition) 2 209 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.47, 1.59]
2 Severe disability (any definition) 1 109 Risk Ratio (M-H, Fixed, 95% CI) 0.54 [0.27, 1.06]
or death
3 Gross motor developmental issue 1 128 Risk Ratio (M-H, Fixed, 95% CI) 1.0 [0.47, 2.14]
(any definition)
4 Steroids for bronchopulmonary 1 203 Risk Ratio (M-H, Fixed, 95% CI) 0.93 [0.65, 1.31]
dysplasia
5 Need for home oxygen 2 270 Risk Ratio (M-H, Fixed, 95% CI) 0.64 [0.30, 1.36]
(survivors)
6 Need for home oxygen (survivors 1 123 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.25, 2.23]
weighing < 1000 g)
Analysis 1.1. Comparison 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) -
subgroup by mode of ventilation, Outcome 1 Death before discharge from hospital.
Comparison: 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by mode of ventilation
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Strict studies
Chowdhury 2013 2/20 2/20 3.2 % 1.00 [ 0.16, 6.42 ]
Comparison: 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by mode of ventilation
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Strict studies
Chowdhury 2013 8/20 11/20 8.2 % 0.73 [ 0.37, 1.42 ]
Comparison: 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by mode of ventilation
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Strict studies
Singh 2006 8/57 11/52 21.2 % 0.66 [ 0.29, 1.52 ]
0.02 0.1 1 10 50
Favours VTV Favours PLV
Comparison: 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by mode of ventilation
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Strict studies
Keszler 2004a 0/9 0/9 Not estimable
Comparison: 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by mode of ventilation
Mean Mean
Study or subgroup Volume targeted Pressure limited Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
1 Strict studies
Lista 2004 (1) 25 8.4 (4.1) 17 11.7 (3.8) 4.0 % -3.30 [ -5.72, -0.88 ]
Keszler 2004a (2) 8 4.5 (7.3) 8 15.6 (18.4) 0.1 % -11.10 [ -24.82, 2.62 ]
Singh 2006 (3) 52 8.4 (12.6) 42 9.7 (14) 0.8 % -1.30 [ -6.75, 4.15 ]
Bhat 2016 20 1.8 (2.9) 20 2.8 (3.3) 6.3 % -1.00 [ -2.93, 0.93 ]
Sinha 1997 (5) 25 5.1 (2.7) 25 6.7 (5.6) 4.0 % -1.60 [ -4.04, 0.84 ]
D’Angio 2005 (6) 90 27.6 (23.8) 94 24 (22.4) 0.5 % 3.60 [ -3.08, 10.28 ]
Liu 2011 31 4.8 (1.1) 30 6.5 (1.9) 38.4 % -1.70 [ -2.48, -0.92 ]
Duman 2012 20 4.06 (5.1) 15 6.93 (7.23) 1.3 % -2.87 [ -7.16, 1.42 ]
Guven 2013 42 3.02 (6.76) 30 6.93 (7.81) 2.0 % -3.91 [ -7.37, -0.45 ]
Erdemir 2014 30 1.05 (1.02) 30 1.68 (1.83) 41.9 % -0.63 [ -1.38, 0.12 ]
-20 -10 0 10 20
Favours VTV Favours PLV
(1) In survivors
(2) In survivors
(3) In survivors
(4) In survivors
(6) In survivors
Comparison: 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by mode of ventilation
Mean Mean
Study or subgroup Volume targeted Pressure limited Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
1 Strict studies
Keszler 2004a 8 0.294 (0.567) 8 0.7 (0.846) 1.3 % -0.40 [ -1.11, 0.30 ]
Lista 2004 25 0.88 (0.208) 17 1.04 (0.159) 53.9 % -0.16 [ -0.27, -0.05 ]
Singh 2006 52 0.486 (0.66) 42 0.43 (0.752) 7.9 % 0.06 [ -0.23, 0.35 ]
Piotrowski 1997 23 0.702 (0.367) 22 0.86 (0.478) 10.7 % -0.16 [ -0.41, 0.09 ]
-1 -0.5 0 0.5 1
Favours VTV Favours PLV
Comparison: 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by mode of ventilation
Mean Mean
Study or subgroup Volume targeted Pressure limited Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
1 Parallel studies
Cheema 2007 21 31.6 (12.9) 19 35.9 (16.2) 1.6 % -4.30 [ -13.44, 4.84 ]
-10 -5 0 5 10
Favours VTV Favours PLV
Comparison: 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by mode of ventilation
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Keszler 2004a 1/9 2/9 10.6 % 0.50 [ 0.05, 4.58 ]
0.02 0.1 1 10 50
Favours VTV Favours PLV
Comparison: 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by mode of ventilation
Outcome: 9 Hypocarbia partial pressure of carbon dioxide (pCO2 ) < 35 mmHg/4.7 kPa
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Comparison: 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by mode of ventilation
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Keszler 2004a 0/9 1/9 11.6 % 0.33 [ 0.02, 7.24 ]
Comparison: 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by mode of ventilation
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Keszler 2004a 6/9 9/9 55.6 % 0.68 [ 0.42, 1.10 ]
0.2 0.5 1 2 5
Favours VTV Favours PLV
Comparison: 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by mode of ventilation
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Strict studies
Lista 2004 22/30 20/23 15.4 % 0.84 [ 0.65, 1.10 ]
0.2 0.5 1 2 5
Favours VTV Favours PLV
Comparison: 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by mode of ventilation
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Strict studies
Lista 2004 2/30 3/23 15.3 % 0.51 [ 0.09, 2.81 ]
0.02 0.1 1 10 50
Favours VTV Favours PLV
Comparison: 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by mode of ventilation
Outcome: 14 Pneumothorax
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Strict studies
Keszler 2004a 0/9 0/9 Not estimable
Comparison: 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by mode of ventilation
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Strict studies
Lista 2004 2/30 2/23 15.2 % 0.77 [ 0.12, 5.04 ]
0.02 0.1 1 10 50
Favours VTV Favours PLV
Comparison: 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by mode of ventilation
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Strict studies
Keszler 2004a 0/8 1/8 1.7 % 0.33 [ 0.02, 7.14 ]
Comparison: 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by mode of ventilation
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Strict studies
Chowdhury 2013 1/20 0/20 2.6 % 3.00 [ 0.13, 69.52 ]
Comparison: 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by mode of ventilation
Risk Risk
Study or subgroup Volume targeted Pressure limited Difference Weight Difference
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Strict studies
Chowdhury 2013 0/20 3/20 5.6 % -0.15 [ -0.32, 0.02 ]
-1 -0.5 0 0.5 1
Favours VTV Favours PLV
Comparison: 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by mode of ventilation
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Strict studies
Keszler 2004a 0/8 1/8 3.2 % 0.33 [ 0.02, 7.14 ]
Comparison: 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by mode of ventilation
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Strict studies
Chowdhury 2013 1/20 3/20 8.1 % 0.33 [ 0.04, 2.94 ]
Comparison: 1 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - subgroup by mode of ventilation
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Strict studies
Chowdhury 2013 11/20 14/20 13.2 % 0.79 [ 0.48, 1.28 ]
Comparison: 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants weighing less than 1000 g
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Strict studies
Lista 2004 2/12 2/5 10.8 % 0.42 [ 0.08, 2.19 ]
0.02 0.1 1 10 50
Favours VTV Favours PLV
Comparison: 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants weighing less than 1000 g
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Strict studies
Keszler 2004a 2/2 4/4 5.0 % 1.00 [ 0.56, 1.79 ]
0.2 0.5 1 2 5
Favours VTV Favours PLV
Comparison: 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants weighing less than 1000 g
Mean Mean
Study or subgroup Volume targeted Pressure limited Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
1 Strict studies
Keszler 2004a 1 5.7 (0) 3 37.3 (6.7) Not estimable
Lista 2004 10 9.9 (5.4) 3 9.7 (2.9) 59.6 % 0.20 [ -4.49, 4.89 ]
Singh 2006 25 13.9 (16.5) 21 16.4 (16.5) 14.3 % -2.50 [ -12.07, 7.07 ]
Piotrowski 1997 8 10.2 (5.7) 5 33.9 (14.9) 7.0 % -23.70 [ -37.34, -10.06 ]
-50 -25 0 25 50
Favours VTV Favours PLV
Comparison: 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants weighing less than 1000 g
Mean Mean
Study or subgroup Volume targeted Pressure limited Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
1 Strict studies
Keszler 2004a 1 0.753 (0) 3 1.57 (0.075) Not estimable
Lista 2004 10 0.938 (0.242) 3 0.97 (0.122) 28.0 % -0.04 [ -0.24, 0.17 ]
Singh 2006 25 0.693 (0.708) 21 0.77 (0.803) 6.0 % -0.07 [ -0.51, 0.37 ]
D’Angio 2005 59 1.475 (0.344) 63 1.32 (0.488) 52.4 % 0.15 [ 0.00, 0.30 ]
-1 -0.5 0 0.5 1
Favours VTV Favours PLV
Comparison: 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants weighing less than 1000 g
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Chowdhury 2013 12/20 16/20 89.5 % 0.75 [ 0.49, 1.14 ]
Analysis 2.6. Comparison 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) -
infants weighing less than 1000 g, Outcome 6 Hypocarbia partial pressure of carbon dioxide (pCO2) < 35
mmHg/4.7 kPa.
Comparison: 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants weighing less than 1000 g
Outcome: 6 Hypocarbia partial pressure of carbon dioxide (pCO2 ) < 35 mmHg/4.7 kPa
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Keszler 2004a 0/2 4/4 100.0 % 0.19 [ 0.01, 2.36 ]
Comparison: 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants weighing less than 1000 g
Outcome: 7 Respiratory acidosis pH < 7.25 and pCO2 > 60 mmHg/8 kPa
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Keszler 2004a 0/2 1/4 9.3 % 0.56 [ 0.03, 9.73 ]
Comparison: 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants weighing less than 1000 g
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Keszler 2004a 0/2 4/4 100.0 % 0.19 [ 0.01, 2.36 ]
Comparison: 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants weighing less than 1000 g
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Strict studies
Lista 2004 12/12 5/5 13.3 % 1.00 [ 0.77, 1.30 ]
Comparison: 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants weighing less than 1000 g
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Strict studies
Keszler 2004a 0/2 0/4 Not estimable
Comparison: 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants weighing less than 1000 g
Outcome: 11 Pneumothorax
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Strict studies
Lista 2004 0/12 1/5 14.3 % 0.15 [ 0.01, 3.25 ]
Comparison: 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants weighing less than 1000 g
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Strict studies
Keszler 2004a 0/2 0/4 Not estimable
Comparison: 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants weighing less than 1000 g
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Strict studies
Keszler 2004a 0/1 1/3 2.4 % 0.67 [ 0.04, 10.05 ]
0.05 0.2 1 5 20
Favours VTV Favours PLV
Comparison: 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants weighing less than 1000 g
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Strict studies
Keszler 2004a 0/1 1/3 5.2 % 0.67 [ 0.04, 10.05 ]
Comparison: 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants weighing less than 1000 g
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Strict studies
Lista 2004 0/12 1/5 20.4 % 0.15 [ 0.01, 3.25 ]
Comparison: 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants weighing less than 1000 g
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Strict studies
Keszler 2004a 0/1 1/3 3.1 % 0.67 [ 0.04, 10.05 ]
Comparison: 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants weighing less than 1000 g
Study or subgroup Volume targeted Pressure limited Odds Ratio Weight Odds Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Strict studies
Keszler 2004a 0/1 1/3 5.2 % 0.56 [ 0.01, 24.51 ]
Comparison: 2 Volume-targeted ventilation (VTV) versus pressure-limited ventilation (PLV) - infants weighing less than 1000 g
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Strict studies
Keszler 2004a 1/1 3/3 5.1 % 1.00 [ 0.41, 2.42 ]
0.05 0.2 1 5 20
Favours VTV Favours PLV
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
D’Angio 2005 13/62 12/62 65.4 % 1.08 [ 0.54, 2.18 ]
Analysis 3.2. Comparison 3 Miscellaneous post hoc analyses, Outcome 2 Severe disability (any definition) or
death.
Review: Volume-targeted versus pressure-limited ventilation in neonates
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Singh 2006 10/57 17/52 100.0 % 0.54 [ 0.27, 1.06 ]
0.2 0.5 1 2 5
Favours VTV Favours PLV
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
D’Angio 2005 11/64 11/64 100.0 % 1.00 [ 0.47, 2.14 ]
Analysis 3.4. Comparison 3 Miscellaneous post hoc analyses, Outcome 4 Steroids for bronchopulmonary
dysplasia.
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
D’Angio 2005 37/99 42/104 100.0 % 0.93 [ 0.65, 1.31 ]
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
D’Angio 2005 5/91 7/94 44.8 % 0.74 [ 0.24, 2.24 ]
0.2 0.5 1 2 5
Favours VTV Favours PLV
Analysis 3.6. Comparison 3 Miscellaneous post hoc analyses, Outcome 6 Need for home oxygen (survivors
weighing < 1000 g).
Study or subgroup Volume targeted Pressure limited Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
D’Angio 2005 5/60 7/63 100.0 % 0.75 [ 0.25, 2.23 ]
0.2 0.5 1 2 5
Favours VTV Favours PLV
Sequence generation (checking for possible selection bias). Was the allocation sequence adequately generated?
For each included study, we categorised the method used to generate the allocation sequence as:
• low risk (any truly random process, e.g. random number table; computer random number generator);
• high risk (any non-random process, e.g. odd or even date of birth; hospital or clinic record number);
• unclear risk.
Allocation concealment (checking for possible selection bias). Was allocation adequately concealed?
For each included study, we categorised the method used to conceal the allocation sequence as:
• low risk (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
• high risk (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);
• unclear risk.
Blinding of participants and personnel (checking for possible performance bias). Was knowledge of the
allocated intervention adequately prevented during the study?
For each included study, we categorised the methods used to blind study participants and personnel from knowledge of which
intervention a participant received. Blinding was assessed separately for different outcomes or class of outcomes. We categorised the
methods as:
• low risk, high risk or unclear risk for participants;
• low risk, high risk or unclear risk for personnel.
Blinding of outcome assessment (checking for possible detection bias). Was knowledge of the allocated
intervention adequately prevented at the time of outcome assessment?
For each included study, we categorised the methods used to blind outcome assessment. Blinding was assessed separately for different
outcomes or class of outcomes. We categorised the methods as:
• low risk for outcome assessors;
Volume-targeted versus pressure-limited ventilation in neonates (Review) 105
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
• high risk for outcome assessors;
• unclear risk for outcome assessors.
Intervention bias (other differences in ventilator management than purely volume-targeted ventilation versus
pressure-limited ventilation).
For each included study, we described whether the only difference between the intervention (ventilator management) was volume-
targeted ventilation (VTV) versus pressure-limited ventilation (PLV). If there were no other obvious differences in the intervention we
defined these studies as ’strict studies.’ In contrast, for some studies there were also other differences between the VTV group and the
PLV group such as use of different ventilators between the groups and use of different triggering modes/devices between groups. These
studies were termed as ’hybrid studies.’
Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol
deviations). Were incomplete outcome data adequately addressed?
For each included study and for each outcome, we described the completeness of data including attrition and exclusions from the
analysis. We noted whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with
the total randomised participants), reasons for attrition or exclusion where reported and whether missing data were balanced across
groups or were related to outcomes. Where sufficient information was reported or supplied by the trial authors, we reincluded missing
data in the analyses. We categorised the methods as:
• low risk (less than 20% missing data);
• high risk (20% or greater missing data);
• unclear risk.
Selective reporting bias. Are reports of the study free of suggestion of selective outcome reporting?
For each included study, we described how we investigated the possibility of selective outcome reporting bias and what we found. We
assessed the methods as:
• low risk (where it was clear that all of the study’s prespecified outcomes and all expected outcomes of interest to the review were
reported);
• high risk (where not all the study’s prespecified outcomes were reported; one or more reported primary outcomes were not
prespecified outcomes of interest and were reported incompletely and so could not be used; study failed to include results of a key
outcome that would have been expected to have been reported);
• unclear risk.
Other sources of bias. Was the study apparently free of other problems that could put it at a high risk of bias?
For each included study, we described any important concerns we had about other possible sources of bias (e.g. whether there was a
potential source of bias related to the specific study design or whether the trial was stopped early due to some data-dependent process).
We assessed whether each study was free of other problems that could put it at risk of bias as:
• low risk;
• high risk;
• unclear risk
If needed, we explored the impact of the level of bias through undertaking sensitivity analyses.
29 June 2017 New citation required but conclusions have not changed A total of eight new studies (8 publications: Zhou 2007;
Liu 2011; Duman 2012; Guven 2013; Chowdhury
2013; Erdemir 2014; Bhat 2016; Jain 2016) were added.
Moreover, additional outcomes from a publication based
on one study (Singh 2006) included in the previous re-
view were added.
The conclusions are not substantially changed.
31 March 2017 New search has been performed This updates the review “Volume-targeted versus pres-
sure-limited ventilation in the neonate” first published
in the Cochrane Database of Systematic Reviews, Issue
3, 2005 (McCallion 2005), and second published ver-
sion in the Cochrane Database of Systematic Reviews,
Issue 4, 2010 (Wheeler 2010).
Searches were conducted in January 2017.
HISTORY
Protocol first published: Issue 2, 2002
Review first published: Issue 3, 2005
27 September 2010 New search has been performed This updates the review “Volume-targeted versus pres-
sure-limited ventilation in the neonate” published in
the Cochrane Database of Systematic Reviews, Issue
3, 2005 (McCallion 2005).
The searches were conducted in January 2010. At to-
tal of six new trials (seven publications) were added:
Piotrowski 2007, Singh 2006 and 2009, D’Angio
2005, Polimeni 2006, Hummler 2006, Cheema 2007.
Supplemental data from authors has been included to
facilitate analysis of duration of ventilation and out-
comes of infants < 1000 g. Pooled meta-analysis iden-
tified a statistically significant reduction in the primary
combined outcome of death and bronchopulmonary
dysplasia favouring volume targeted ventilation. The
conclusions have been revised
27 September 2010 New citation required and conclusions have changed Wheeler K, Klingenberg C added to authorship.
The conclusions have been revised.
1 April 2005 New citation required and conclusions have changed Substantive amendment
CONTRIBUTIONS OF AUTHORS
NMC: wrote the protocol with assistance from CJM and PGD.
For the 2005 review, NMC wrote the review with assistance from PGD and CJM.
For the 2010 update, KIW and CK performed the search, assessed articles, liaised with study authors regarding supplemental information,
extracted and analysed data. PGD supervised the research. CJM and NMC assisted with reviewing the manuscript.
For the 2017 update, KIW and CK performed the search, assessed articles, liaised with study authors regarding supplemental information,
extracted and analysed data. CK and KIW wrote the review. PGD, CJM and NMC assisted with reviewing the manuscript.
DECLARATIONS OF INTEREST
CJM: has acted as a consultant to Drager Medical and Acutronic Medical Instruments, both manufacturers of neonatal ventilators.
The companies had no involvement with the funding, design or conduct of this review.
CK: None
KIW: None
PGD: None
NMC: None
SOURCES OF SUPPORT
Internal sources
• Royal Women’s Hospital Foundation, Melbourne, Australia.
• Murdoch Children’s Research Institute, Melbourne, Australia.
External sources
• No sources of support supplied
• Subgroup analysis for strict versus hybrid trial designs, within Analyses 1 and 2 where applicable.
The following outcomes included above were not included in the original protocol for this review.
We also added the methodology and plan for ’Summary of findings’ tables and GRADE recommendations, which were not included
in the original protocol or previous versions of the review.
INDEX TERMS